tbuckley/cabot-search huggingface dataset:
Sex-specific effects of daily tadalafil on diabetic heart kinetics in RECOGITO, a randomized, double-blind, placebo-controlled trial
Authors: Riccardo Pofi, Elisa Giannetta, Tiziana Feola, Nicola Galea, Federica Barbagallo, Federica Campolo, Roberto Badagliacca, Biagio Barbano, Federica Ciolina, Giuseppe Defeudis, Tiziana Filardi, Franz Sesti, Marianna Minnetti, Carmine D. Vizza, Patrizio Pasqualetti, Pierluigi Caboni, Iacopo Carbone, Marco Francone, Carlo Catalano, Paolo Pozzilli, Andrea Lenzi, Mary Anna Venneri, Daniele Gianfrilli, Andrea M. Isidori
Journal: Science Translational Medicine (2022)

Cyclic GMP–phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (&gt;3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c &lt; 86 mmol/mol) were selected according to echocardiographic signs of cardiac remodeling. Patients were randomly assigned (1:1) to placebo or oral tadalafil (20 mg, once daily). The primary outcome was to evaluate sex differences in cardiac torsion change. Secondary outcomes were changes in cardiovascular, metabolic, immune, and renal function. At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion (−3.40°, −5.96; −0.84, P = 0.011) and fiber shortening (−1.19%, −2.24; −0.14, P = 0.027) in men but not women. The primary outcome could not be explained by differences in cGMP concentrations or tadalafil pharmacodynamics. In both sexes, tadalafil improved hsa-miR-199-5p expression, biomarkers of cardiovascular remodeling, albuminuria, renal artery resistive index, and circulating Klotho concentrations. Immune cell profiling revealed an improvement in low-grade chronic inflammation: Classic CD14 ++ CD16 − monocytes reduced, and Tie2 + monocytes increased. Nine patients (14.5%) had minor adverse reactions after tadalafil administration. Continuous PDE5 inhibition could offer a strategy to target cardiorenal complications of T2DM, with sex- and tissue-specific responses. Further studies are needed to confirm Klotho and hsa-miR-199-5p as markers for T2DM complications.
Abstract 5169: Sentinel lymph node gene expression signature predicts survival outcome in cutaneous melanoma
Authors: Lilit Karapetyan, William Gooding, Xi Yang, Andrew Knight, Aofei Li, Cindy Sander, Monica Panelli, Walter J. Storkus, Ahmad A. Tarhini, John M. Kirkwood
Journal: Cancer Research (2022)

Abstract Background: Sentinel lymph node status is an important prognostic factor for melanoma progression. We sought to develop a sentinel lymph node gene expression signature score predictive of disease progression in patients with cutaneous melanoma. Methods: Cases were retrieved from University of Pittsburgh protocol “Sentinel Node and Non-Sentinel Lymph Nodes (SLN and non-SLN) Procurement from Melanoma Subjects for Molecular Profiling.” Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. The top 25 genes associated with progression-free survival (PFS) were selected and a penalized regression function was used to select genes with a non-zero coefficient. A risk score was calculated from a 12 gene signature. A proportional hazards regression model was used to evaluate the association between clinical covariates, gene signature score, and PFS. Results: In total, 45 patients were included [female=18 (40%), median age (range)= 56 (16-81) years]. The median Breslow thickness (IQR) was 4.1 (3.3-6.0) mm, ulceration was present in 29 (67%) cases, and 25 (56%) lesions had nodular histology. Among patients, 23 (51%) had a positive SLN via H&amp;E. Twenty-one (46.7%) patients developed disease recurrence/progression with a median follow-up of 8.3 years. The median time to progression was 9.6 years. Among the top 25 genes, 12 non-zero penalized coefficients were estimated (CLGN, C1QTNF3, ADORA3, ARHGAP8, ZNF223, PDE6G, CXCL3, CHRFAM7A, HLA-DRB-decreased risk, DCTN1, ASPSCR1, HEXIM1-increased risk). A 12-gene signature score was significantly associated with PFS (p&amp;lt;0.0001) and produced a bootstrap cross-validated C index of 0.888. Stratifying by SLN status the gene signature risk score remained highly significant (p&amp;lt;0.0001). In univariate analysis, Breslow thickness (HR=1.41), presence of ulceration (HR=3.61), SLN positivity (HR=2.50), and acral-lentiginous histology compared to nodular (HR=4.07) were each significantly associated with PFS (all p&amp;lt;0.05). After simultaneously adjusting for all of these factors plus the gene signature, the 12-gene score remained a significant predictor for PFS (p&amp;lt;0.0001). Conclusion: A SLN 12-gene signature risk score is associated with melanoma progression regardless of SLN status and can be used as a prognostic factor for PFS of patients. External validation of the gene signature is warranted. Citation Format: Lilit Karapetyan, William Gooding, Xi Yang, Andrew Knight, Aofei Li, Cindy Sander, Monica Panelli, Walter J. Storkus, Ahmad A. Tarhini, John M. Kirkwood. Sentinel lymph node gene expression signature predicts survival outcome in cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5169.
Abstract 379: Application of NanoBRET target engagement cellular assay for measurement of inhibitor binding to wild type and mutant RAS in live cells
Authors: Jianghong Wu, Shawn McGinley, Yuan Wang, Peter Gallagher, Haiching Ma
Journal: Cancer Research (2022)

Abstract NanoBRET࣪ target engagement (TE) is the first biophysical technique that broadly enables the quantitative determination of protein inhibitor occupancy in live cells, without disruption of cellular membrane integrity. This quantitative capability is achieved in live cells via BRET with an optimized set of cell-permeable tracers, allow the measurement of compound binding to a selected cellular target protein. RAS is a well-known oncogene that is frequently mutated in most lung, pancreatic and colorectal cancers and is associated with poor disease prognosis. Mutated RAS is locked in the activated GTP bound state and facilitates enhanced RAS signaling in cancer cells. While being a desirable target, the absence of good druggable binding pockets has made modulator compound discovery challenging and unsuccessful. The recent discovery of a unique switch II binding pocket and successful inhibition of the KRAS (G12C) mutant by covalent inhibitors have led to the resurgence of interest in the design of inhibitors targeting RAS directly. Here, we performed NanoBRET࣪ TE cellular assay with RAS inhibitors against transfected RAS and its mutants. Our data demonstrate that NanoBRET࣪ TE cellular assay can measure the apparent affinity of RAS inhibitors by competitive displacement of a NanoBRET࣪ RAS switch I/II pocket tracer, reversibly bound to the LgBiT- and SmBiT- KRAS, KRAS (G12C), KRAS (G12D), KRAS (G12V), KRAS (G13D), KRAS (Q61H), KRAS (Q61L), KRAS (Q61R), or HRAS fusion constructs co-transfected in live HEK293 cells. Z factor analysis indicates the assay is High Throughput Screening (HTS) compatible and reproducible. In addition, we are able to confirm the signaling inhibition of downstream phospho-ERK1/2 by KRAS (G12C)-specific inhibitors AMG 510 (Sotorasib), ARS-1620, MRTX849, and MRTX1257 in MIA PaCa-2 pancreas and SW837 colon cancer cells bearing KRAS (G12C) mutation by Western blot assay. Our results suggest NanoBRET࣪ TE cellular assay can serve as a great tool to facilitate RAS pathway drug discovery against human cancers. Citation Format: Jianghong Wu, Shawn McGinley, Yuan Wang, Peter Gallagher, Haiching Ma. Application of NanoBRET target engagement cellular assay for measurement of inhibitor binding to wild type and mutant RAS in live cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 379.
Abstract 6320: Connecting TET2 deficiency with inflammation in CMML and anti-tumor responses
Authors: Anup Kumar Singh, Atsushi Onodera, Hugo Sepulveda, Carlos Angel, Anjana Rao
Journal: Cancer Research (2022)

Abstract Chronic Myelomonocytic Leukemia (CMML) is a clonal hematologic disorder of older individuals characterized by monocytosis and increased risk of progression to acute myeloid leukemia (AML). Although CMML is characterized by relatively low genetic complexity consistent with clonal expansion, loss-of-function mutations in ten-eleven translocation 2 (TET2) protein are frequent and reported in almost 60% of CMML cases. Consistent with this finding, deletion of the Tet2 gene in mice leads to CMML-like disease. TET2 restrains inflammatory signals through various means, for instance by directly suppressing the expression of the IL6 gene in mouse myeloid cells by recruiting histone deacetylases. Conversely, the levels of pre-inflammatory cytokines including IL6 correlate with pre-leukemic proliferation of Tet2-deficient mouse monocytes and other myeloid cells, suggesting that Tet2 deficiency increases IL-6 expression and increased IL-6 expression in turn drives the proliferation of Tet2-deficient myeloid-lineage cells in a positive feedback loop. This scenario may operate in CMML patients, who show increased levels of inflammatory cytokines and increased expression of interferon-induced genes compared to age-matched healthy individuals. To gain insight into the connection between inflammation caused by TET deficiency and monocyte hyperproliferation, we set up cultures of bone marrow derived macrophages (BMDMs) from inducible TET deficient mice. Using this model, we found that TET-deficient BMDMs show increased proliferation compared to wild type controls; moreover, LPS stimulation leads to significantly increased expression of IL6 and IL1b in TET-deficient BMDMs. Our previous RNA sequencing of expanded TET-deficient myeloid cells in vivo showed that TET deficiency correlated with increased expression of transposable elements (TEs) and induced a DNA damage response, leading us to hypothesize that TET deficiency and increased TE expression may activate DNA and RNA sensing pathways and induce sterile inflammation. I am currently using several molecular approaches to delineate the potential connection of TET deficiency with endogenous inflammation in CMML. There is growing evidence that TET deficiency or non-specific inhibition of TET enzymes in CD8 T cells can potentiate anti-tumor responses. I am now asking whether the TET deficiency-inflammation axis I observe in BMDMs might also enhance anti-tumor responses by increasing proinflammatory responses and hence T cell recruitment and anti-tumor activity. Citation Format: Anup Kumar Singh, Atsushi Onodera, Hugo Sepulveda, Carlos Angel, Anjana Rao. Connecting TET2 deficiency with inflammation in CMML and anti-tumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6320.
Abstract 6088: Reconstructing mutational lineages in breast cancer by multi-patient-targeted single cell DNA sequencing
Authors: Jake Leighton, Min Hu, Emi Sei, Funda Meric-Bernstam, Nicholas Navin
Journal: Cancer Research (2022)

Abstract Single cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells, however most genomic regions characterized in single cells are non-informative. To overcome this issue, we developed a Multi-Patient-Targeted (MPT) scDNA-seq sequencing method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 TNBC patients, which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From this data, we reconstructed mutational lineages and identified early mutational and copy number events, including early TP53 mutations that occurred in all five patients. Collectively, our data suggests that MPT can overcome technical obstacles for studying tumor evolution using scDNA-seq by profiling information-rich mutation sites. Citation Format: Jake Leighton, Min Hu, Emi Sei, Funda Meric-Bernstam, Nicholas Navin. Reconstructing mutational lineages in breast cancer by multi-patient-targeted single cell DNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6088.
Abstract 5192: Efficacy and safety of second-line therapy by S-1 combined with Sintilimab and Anlotinib in pancreatic cancer patients with liver metastasis: A single-arm, phase II clinical trial
Authors: Juan Du, Xin Qiu, Changchang Lu, Huizi Sha, Yahui Zhu, Weiwei Kong, Xing Li, Xiaoping Qian, Baorui Liu
Journal: Cancer Research (2022)

Abstract Background: The mortality of pancreatic cancer is increasing year by year, and the prognosis of pancreatic cancer with liver metastasis is worse. There is still no recognized effective second-line treatment strategy. In this trial, the efficacy and safety of the triple-drug regimen by S-1 chemotherapy combined with anti-PD-1 McAb (Sintilimab) and anti-angiogenic drug (Anlotinib) were evaluated in pancreatic cancer patients with liver metastasis. Methods: Pancreatic cancer patients with liver metastases and ECOG 0~2 were recruited. These patients had never been given 5-FU, anti-PD-1 McAb and/or anti-angiogenic drugs in first-line treatment. S-1 was administered orally at 25 mg/m2 bid from day 1 to day 14, Sintilimab was administered intravenously at 200 mg on day 1, and Anlotinib was administered orally 12mg qd from day 1 to day 14. This method were repeated every 21 days till disease progression. The therapeutic effect was evaluated every 3 cycles. Progression-free survival (PFS) and overall survival (OS) were estimated via the K-M method. Some patients’ tumor tissues have done high-throughput sequencing and the relationship between with effect has been analyzed. Results: From March 2020 to June 2021, a total of 23 patients were enrolled in this study and 19 patients had objective efficacy evaluation. Two patient (10.5%) had confirmed partial response and eight patients (42.1%) had stable disease. Median PFS and OS were 3.53 months and 7.15 months. Grade 3 adverse events were 26.3%, and there were no grade 4 or above adverse events. The tumor tissues of 16 patients have done high-throughput sequencing, and genetic test results show that 6 patients were evaluated as HRD-High and 10 patients as HRD-Low. Patients with HRD-H had shorter PFS than those with HRD-L (2.43 vs. 5.45 months; p = 0.043), However, OS was not significantly different between these two groups (4.43vs.9.35 months; P = 0.11). Conclusions: This study suggests that S-1 chemotherapy combined with anti-PD-1 McAb (Sintilimab) and anti-angiogenic drug (Anlotinib) is efficacy and safety as a second-line treatment for pancreatic cancer patients with liver metastasis. Subgroup analysis showed that patients with HRD-L had longer PFS. HRD-H were found to be related to worsen PFS, which may indicate that other therapies should be explored regarding to these patients. Citation Format: Juan Du, Xin Qiu, Changchang Lu, Huizi Sha, Yahui Zhu, Weiwei Kong, Xing Li, Xiaoping Qian, Baorui Liu. Efficacy and safety of second-line therapy by S-1 combined with Sintilimab and Anlotinib in pancreatic cancer patients with liver metastasis: A single-arm, phase II clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5192.
Abstract 3269: Dual targeting of FLT3 and LSD1 disrupts the MYC super-enhancer complex in acute myeloid leukemia
Authors: William M. Yashar, Brittany M. Smith, Jake VanCampen, Garth L. Kong, Jommel Macaraeg, Daniel J. Coleman, Brian J. Druker, Julia E. Maxson, Theodore P. Braun
Journal: Cancer Research (2022)

Abstract Clinical responses to kinase inhibitor therapy in acute myeloid leukemia (AML) are limited by development of resistance. A major contributor of resistance is epigenetic adaptation to kinase inhibitor therapy. We present evidence that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) augments the response to inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-mutant AML. We demonstrate that combined FLT3 and LSD1 inhibition results in synergistic cell death of FLT3-mutant AML cell lines and primary patient samples. High-resolution epigenetic sequencing revealed that the combination therapy synergistically suppresses pro-proliferative MYC-bound promoters and activates pro-differentiative PU.1-bound enhancers. Regulon enrichment analysis in primary AML samples nominated STAT5 (a downstream target of activated FLT3 signaling) as a putative regulator of MYC gene expression. STAT5 is highly bound to the MYC blood super-enhancer and FLT3 inhibition results in a loss of both STAT5 binding and MYC blood super-enhancer chromatin accessibility. In contrast, LSD1 inhibition suppresses MYC target genes by accumulation of repressive H3K9me1 marks. We validated these findings in 72 primary AML samples, including 19 FLT3-ITD positive AML samples. The combination improved responses in the vast majority of patient samples, and high MYC regulon activity was a predictor of response. Gene expression profiling in treated primary AML samples confirmed that dual FLT3 and LSD1 inhibition activates PU.1 target genes and suppresses MYC target genes. Finally, single cell ATAC-seq on primary AML blasts treated ex vivo with combined FLT3 and LSD1 shifted cells from a MYC super-enhancer high to MYC super-enhancer low state. Collectively, these data provide preclinical rationale for the investigation of dual FLT3 and LSD1 inhibition in clinical trial. Citation Format: William M. Yashar, Brittany M. Smith, Jake VanCampen, Garth L. Kong, Jommel Macaraeg, Daniel J. Coleman, Brian J. Druker, Julia E. Maxson, Theodore P. Braun. Dual targeting of FLT3 and LSD1 disrupts the MYC super-enhancer complex in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3269.
Abstract 3652: Maternal body mass index, diabetes, and gestational weight gain and risk for pediatric cancer in offspring: A systematic review and meta-analysis
Authors: Andrew R. Marley, Allison Domingues, Taumoha Ghosh, Lucie M. Turcotte, Logan G. Spector
Journal: Cancer Research (2022)

Abstract Introduction: Pediatric cancer incidence has steadily increased concurrent with the rise in adult obesity, however, associations between maternal obesity and associated comorbidities and pediatric cancer risk remain understudied. Methods: A comprehensive and systematic literature search in PubMed and EMBASE databases from their inception to March 15th, 2021. Eligible studies reported risk estimates, sample sizes, and provided sufficient description of outcome and exposure ascertainment. Studies were excluded if not complete, published, peer-reviewed studies, or if provided incompatible exposure data. Data quality was assessed according to Newcastle-Ottawa Scale (NOS) guidelines and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Random-effects models were used to estimate pooled effects. Results: Thirty-four studies were included, covering 3,404,747 subjects and 14,706 pediatric cancer cases for pre-pregnancy BMI; 14,748,772 subjects and 44,628 pediatric cancer patients for maternal diabetes; and 2,124,647 participants and 15,915 pediatric cancer cases for gestational weight gain. Pre-pregnancy BMI was significantly associated with leukemia risk in offspring (OR per 5-unit BMI increase =1.07 [95% CI = 1.04-1.11] I2 = 0.0%). Any maternal diabetes was positively associated with acute lymphoblastic leukemia risk (OR=1.46 [95% CI = 1.28-1.67] I2 = 0.0%), even after restricting to birthweight-adjusted analyses (OR [95% CI] = 1.74 [1.29-2.34] I2 = 0.0%), and inversely associated with risk of central nervous system tumors (OR=0.73 [95% CI = 0.55-0.97] I2 = 0.0%). Pre-gestational diabetes (OR=1.57 [95% CI = 1.11-2.24] I2 = 26.8%) and gestational diabetes (OR=1.40 [95% CI = 1.12-1.75] I2 = 0.0%) were also significantly associated with acute lymphoblastic leukemia risk. No significant associations were observed for gestational weight gain and pediatric cancer risk. Conclusions: Maternal obesity and diabetes may be etiologically linked to pediatric cancer, particularly leukemia and central nervous system tumors. Our findings support appropriate weight management and glycemic control as important components of maternal care and offspring health. Further validation studies are warranted. Citation Format: Andrew R. Marley, Allison Domingues, Taumoha Ghosh, Lucie M. Turcotte, Logan G. Spector. Maternal body mass index, diabetes, and gestational weight gain and risk for pediatric cancer in offspring: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3652.